A variety of medical conditions affect the ability of heart muscle to properly contract in response to electrical stimulus—either intrinsic stimulus generated by the sinus node and conduction system of the heart or therapeutic pacing pulses delivered by a pacemaker or other implantable cardiac stimulation device. In particular, various cardiomyopathies of differing etiologies can affect myocardial contractility, and the temporal relationships of motion/contractility of various regions (dysynchrony). These effects can be secondary to a combination of primary disturbances in electrical conduction and pathologic myocardial tissue.
Cardiomyopathy, i.e. “heart muscle disease”, pertains to the deterioration of the function of the myocardium. Cardiomyopathy often results in heart failure as the pumping efficiency of the heart is diminished. Patients with cardiomyopathy are often at risk for arrhythmia and/or sudden cardiac death (typically due to ventricular fibrillation). Some cardiomyopathies are deemed extrinsic, whereas others are intrinsic.
Extrinsic cardiomyopathies are those in which the primary pathology is outside the myocardium itself and include such cardiomyopathies as ischemic cardiomyopathy, hypertensive cardiomyopathy, valvular cardiomyopathy, inflammatory cardiomyopathy and cardiomyopathy secondary to systemic diseases. Of these, the most common is ischemic cardiomyopathy, which pertains to weakness in the myocardium due, e.g., to coronary artery disease. Patients with ischemic cardiomyopathy often have a history of acute myocardial infarction (i.e. heart attack), although chronic ischemia can cause sufficient damage to the myocardium to cause a clinically significant cardiomyopathy even in the absence of myocardial infarction. Typically, the area of the heart affected by a myocardial infarction becomes necrotic and is replaced by scar tissue (fibrosis). Fibrotic tissue is “akinetic”, i.e. it no longer functions as muscle and hence does not contribute to the heart's pumping function. In many cases, the affected side of the heart (i.e. the left side or the right side) will go into failure. Heart failure that is sufficiently severe is referred to as congestive heart failure (CHF), which is a frequent cause of mortality in elderly patients. Intrinsic cardiomyopathy, in contrast, pertains to a weakness in the myocardium that is not due to an identifiable external cause.
Intrinsic cardiomyopathy can arise due to certain infections (including Hepatitis C, Coxsackie viruses), and various genetic and idiopathic (i.e., unknown) causes as well as from alcohol and drug use. Exemplary types of intrinsic cardiomyopathies include dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy and restrictive cardiomyopathy.
In general, with diseased myocardium, there is a combination of denervation or impairment of the normal physiologic conduction system, myocardial stunning, hibernation and cell death. (Myocardial stunning is the phenomenon in which brief, reversible episodes of ischemia leave a prolonged depression of cardiac function that recovers only slowly over several hours or days.) Myocardial stunning, hibernation and cell death lead to hypocontractility, i.e. reduced contractility. Reduced contractility often results in a loss of cardiac output and also a lack of synchronous depolarization, i.e. a lack of coordination between the left and right chambers, atrial and ventricular chambers or within the left ventricular chamber itself (intra-ventricular dysynchrony). These impairments are often segmental, i.e. regional rather than global, especially in patients with ischemic heart disease.
As can be appreciated, the impairment in myocardial contractility arising from cardiomyopathy or other causes can significantly impair the functioning of the heart, leading to debilitated lifestyle and, in all too many cases, death. Accordingly, it would be highly desirable to remedy or mitigate any loss of contractility and reduce dysynchronous electro-mechanical activation. Various pharmacological treatments are available but these tend to affect the entire myocardium and do not target particular parts of the heart that may be impaired, i.e. the treatments do not specifically address segmental impairments. Many patients with impaired myocardial contractility have pacemakers, implantable cardioverter-defibrillators (ICDs) or other medical devices implanted therein that permit electrical stimulation to be selectively delivered to particular portions or chambers of the heart. Accordingly, techniques have been developed that seek to improve myocardial contractility using such devices by delivering non-pharmacologic inotropic therapy (NPIT) and improving synchronous electro-mechanical activation with Cardiac Resynchronization Therapy (CRT). CRT is the sum and substance of currently implanted biventricular pacing systems. NPIT is not yet widely available and still is under investigational study. However, a wealth of literature exists, which demonstrate the benefits of CRT for improving heart failure symptoms and even reducing mortality (see, e.g., the “Cardiac Resynchronization in Heart Failure” study, i.e. the “CARE-HF” study, Cleland et al. on behalf of The CARE-HF study Steering Committee and Investigators, “The CARE-HF study (CArdiac REsynchronisation in Heart Failure study): Rationale, Design and End-points, Eur Heart J, 2001; 3: 481-489). CRT is also discussed in, for example, U.S. Pat. No. 6,643,546 to Mathis, et al., entitled “Multi-Electrode Apparatus and Method for Treatment of Congestive Heart Failure”; U.S. Pat. No. 6,628,988 to Kramer, et al., entitled “Apparatus and Method for Reversal of Myocardial Remodeling with Electrical Stimulation”; and U.S. Pat. No. 6,512,952 to Stahmann, et al., entitled “Method and Apparatus for Maintaining Synchronized Pacing”.
Techniques for delivering non-excitory inotropic stimulation to the heart in an effort to improve contractility are just emerging. See, for example, U.S. Pat. No. 6,233,484 to Ben-Haim et al. entitled “Apparatus and Method for Controlling the Contractility of Muscles” and related patents and patent applications of Impulse Dynamics N.V. The techniques described therein generally involve delivering relatively high voltage electrical stimulation pulses during a refractory period (during which the myocardium is not capable of contracting in response to electrical stimulation). The stimulation pulses are apparently intended to enhance calcium flux so as to improve contractility such that subsequent contractions are more hemodynamically effective.
Although refractory period-based inotropic techniques appear to be promising, it is believed that effective inotropic treatment can also be obtained by selectively delivering electrical stimulation outside of the refractory period, and it is to this end that certain aspects of the present invention are directed. In particular, it is desirable to provide techniques for applying subthreshold inotropic stimulation (i.e. stimulation below a threshold sufficient to trigger depolarization of the myocardium) outside the refractory period for the purposes of improving myocardial contractility. Among other potential advantages, subthreshold stimulation generally uses less power than the comparatively high voltage refractory period-based inotropic stimulation and hence does not significantly deplete battery power. Other aspects of the invention pertain to techniques for delivering suprathreshold inotropic stimulation (i.e. electrical stimulation above the threshold necessary to trigger depolarization) outside refractory periods and at the appropriate times to reduce dysynchronous activation patterns. Still other aspects of the invention are applicable to providing improvements to refractory period-based inotropic stimulation. Thus, the technologies described offer a combined approach to regionally improve contractility and reduce electromechanical dysynchrony in territories that have pathologic contractility and conductivity and allow normal tissue to function unaffected. These device based therapies are implemented when and where needed based, e.g., on repeated measurements of impedance based metrics that reflect contractile and conductive cardiac properties.